Project Summary The goal of this proposal is to evaluate the feasibility of using HMGCR inhibitors (statins) to enhance efficacy of ABT-199 in preclinical models of B cell cancers. ABT-199 (venetoclax) is a small molecule inhibitor of BCL-2, a key pro-survival protein that is highly expressed in many leukemias and lymphomas. Statins are commonly used to control plasma cholesterol levels and are among the most widely prescribed medications worldwide. However, statins are also known to have anti-cancer potential. We have observed potent synergy of statins combined with ABT-199 in human cell lines derived from diffuse large B cell lymphoma (DLBCL). This synergy is also seen in murine B lymphoma cells derived from a genetically engineered mouse model. Using a BH3 profiling assay, we observed that simvastatin increases mitochondrial priming, correlating with its ability to synergize with ABT-199. Mechanistic studies support the hypothesis that statins prime lymphoma cells for apoptosis by blocking prenylation pathways downstream of mevalonate production by HMG-CoA-reductase. In this proposal we will build on these findings to address the feasibility of the statin/ABT-199 combination. The first Aim is to determine whether statins can achieve pharmacological exposure in tumor cells at a clinically relevant dose. We will compare three different statins in a mouse lymphoma model to identify the optimal statin and minimal dose with pharmacodynamic activity. The second Aim will be to evaluate the efficacy and toleratibility of the statin/ABT-199 combination in lymphoma models. Using a mouse syngeneic B cell lymphoma driven by BCL-2 and MYC, we will assess differences in lymphoma outgrowth and mouse survival, and correlate with a pharmacodynamic marker of statin action. We will also examine drug effects on survival of primary human lymphoma cells in vitro. In parallel we will measure the impact of drug treatments on normal lymphocytes using both the in vivo mouse model, and using peripheral blood mononuclear cells from healthy human volunteers. The third Aim is to test whether mitochondrial priming provides a predictive biomarker of statin efficacy. Using dynamic BH3 profiling, we will determine whether increased mitochondrial priming by statins correlates with response to the statin/ABT-199 combination. Together these experiments will establish efficacy, tumor selectivity, and a predictive biomarker for the combination of statins plus ABT-199, providing proof-of-concept to support future clinical trials in aggressive lymphomas.